A growing body of evidence is emerging from studies in animal and cellular model systems that indicates that the effects of ethanol on a variety of cellular functions are mediated by changes in specific proteins. In these systems, however, it is difficult to establish whether these proteins directly or indirectly mediate ethanol-induced changes in nervous system function. It is therefore important to establish a simple model system for alcoholism that is easily accessible to genetic and molecular analyses. We have recently initiated studies using the fruit fly Drosophila as a potential model system for.alcoholism. Preliminary studies have shown that flies display many of the behaviors observed in humans after both acute and chronic exposure to ethanol. Flies display signs of hyperactivity and incoordination, followed by sedation and anesthesia. In addition, flies develop tolerance after single or multiple exposures to ethanol. We propose to generate and isolate Drosophila mutants that have altered responses to ethanol. For this purpose an "inebriometer" has been constructed, which allows the separation of flies with different sensitivity to ethanol. A genetic screen for mutants with increased or decreased sensitivity to an acute ethanol exposure will be carried out. In addition, mutant flies that fail to become tolerant or become excessively tolerant to ethanol will be isolated. Several secondary behavioral assays will be carried out to determine whether the phenotype is ethanol-specific and whether the focus of the mutation is in the central nervous system. Mutations will be mapped to specific chromosomal locations. Some of the genes affected will be isolated and sequenced. These genes will serve as tools to study molecular and biochemical mechanisms underlying ethanol-induced responses, and may in the future serve as genetic markers for alcoholism or targets for potential therapeutic intervention.